Aminoalkyl esters of alpha,alpha-diaryl-gamma,delta-unsaturated aliphatic acids and the production thereof



Patented Nov. 25, 1952 UNITED STATES PATENT {OFFICE Carl .Peter Krimmel, Evanston, 111., assignor to G. D.-Sear1e & 00., Chicago, 111., a corporation of Illinois N0 Drawing. Application December 10, 1949, Serial No. 132,401

01. zen-res) 18 Claims.

1 This-invention relates to aminoalkyl esters of a,a-'diaryl d-unsaturated aliphatic acids, to salts thereof and to methods of producing such compounds. In particular-this invention relates to basic esters having the general structural formula wherein R and R. are lower alkyl radicals or hydrogen, Ar and Ar are monocyclic aromatic carbocyclic radicals, Alk is alower alkylene radical, and X and X are lower alkyl radicals.

The compounds of this invention are useful as medicinal agents. Certain of them are active as spasmolytic agents, while others are useful as local anesthetics and as adrenolytic and autonomic blocking agents. The compounds of this invention are also useful as intermediates in the formation of more complex basic esters for therapeutic and pharmacological purposes.

In the foregoing structural formula R and'R represent hydrogen or the same or different lower alkyl radicals such as methyl, ethyl, propyl, and isopropyl radicals. Ar and Ar include aromatic carbocyclic radicals such as phenyl, tolyl, xenyl, and related homologues, and chlorophenyl, bromophenyl, iodophenyl, methoxyphenyl, ethoxyphenyl, hydroxyphenyl "and related monocarbocyclic aromatic radicals. Thealkylene radical, Alk, is a bivalent radical containing 2 to 8 carbon atoms derived from a saturated-aliphatic hydrocarbon and includes ethylene, propylene, trimethylene, tetramethylene, hexamethylene, octamethylene, 2,3-butylene, 1,3-butylene, 1,2-butylene, and similar bivalent aliphatic hydrocarbon radicals. X and X represent the same or different lower alkyl radicals and comprise alkyl radicals containing 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl and octyl radicals.

The basic esters of this invention are usually viscousoils which arev insoluble in water but soluble in common organic solvents such as ether, halogenated hydrocarbons, hydrocarbons, lower alcohols, ketones, and esters. The compounds are useful both in the form of the free bases or as acid addition or quaternary ammonium salts, The bases form stable salts with a variety of inorganic and strong organic acids. These salts are generally soluble in water, and therefore constitute a preferred form of the invention. Among the acids which are suitable for forming acid addition salts'are' hydrochloric, hydrobromic, hydriodic, sulfuric, sulfamic, phosphoric, citric,

tartaric, malic, maleic, succinic. benzene-.sulfonic, tcluene-sulfon-ic, lactic, oxalic, acetic, propionic, gluconic,.benzoic, ,cinnamic, and related acids.

The organicbases also form quaternary ammonium salts whentreated with an alkyl, alkenyl, hydroxyalkyl oraralkyl ester of a halogen acid, sulfuric acid or an aromatic sulfonic acid. Among such esters are methyl:chloride, methyl iodide, ethyl bromide, ethylchloride, allyl chloride, allyl bromide, ,crotyl chloride, methallyl bromide, ethylene chlorohydrin, ethylene bromohydrin, npropyl chloride, benzyl chloride, benzylbromide, methyl benzenesulfonate, ethyl toluene'sulfonate, naphthylmethyl chloride, dimethyl sulfate, diethyl sulfate, and related esters. The quaternary ammonium salts of thebasic esters of this invention are generallycrystalline-stable solids which are readily soluble inwater andaqueous solutions. The quaternary ammonium saltsygenerally exhibit physiological activities which are different from those of the tertiarybases. For example, many of the quaternary ammonium salts are adrenergic agents, whereas the tertiary bases are not.

Compoundsof this invention-may be made by a variety of methods. The organic acid of the formula may be converted to the corresponding acid halide or acid anhydride by treatment with thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, acetic anhydride, or similar reagents, and the resulting acid derivative may be condensed with a dialkylaminoalkanol of the formula wherein Alk, 'X and 1X have the meanings-given hereinabove. The basic ester is formed directly and may .beisolatedxby conventional methods of organic chemistry. The esters may also be producedby reacting .an alkali metal salt of the organicacid .of theforegoing formula with an aminoalkyljhalide ofxthe formula wherein Z represents a halogen of atomic number greater than .9, preferably .a middle halogen such as chlorine or bromine. An alternative method of production of the esters of thisinvention involves the-heating of the organic acid of the foregoing type with an aminoalkyl halide of the formula given hereinabove, in a solvent such as acetone, isopropanol, ethanol, methyl ethyl ketone and related water-miscible organic liquids. During this reaction the elements of hydrogen halide are split out with the formation of a basic ester as its hydrohalide salt. The oranic bases are isolated from the reaction mixture by neutralization and extraction and are generally purified by distillation under reduced pressure. In certain instances the salts of the basic esters, which form during the reaction mixture, are crystalline substances which precipitate from the reaction mixture and may be separated and purified as such.

The following examples illustrate in more detail my invention without limiting it in spirit or in scope. It will be obvious to those skilled in the art that numerous modifications relating to temperature, proportions, solvents, and other reaction conditions may be made without departure from the invention. Similarly, related amino alcohols or acids may be used without deviating from the scope of the invention. The relative amounts of materials are given in parts by weight.

Example 1 320 parts of c-methallyldiphenylacetic acid, 163 parts of fl-diethylaminoethyl chloride and 4000 parts of anhydrous isopropanol are refluxed and agitated for five hours. The solvent is stripped off under vacuum at steam temperature and the residue of B-diethylaminoethyl B-methallyldiphenylacetate hydrochloride is taken up in water. The water solution is extracted with ether to remove insoluble materials. The aqueous solution is made alkaline, and the organic base is extracted with ether. The ether solution is treated with anhydrous potassium carbonate, filtered and evaporated. The residue of fl-diethylaminoethyl 18-methallyldiphenylacetate is distilled at 205-210 C. at 2 mm. pressure. parts of the basic ester in 560 parts of anhydrous ether are treated with an equivalent of anhydrous hydrogen chloride in isopropanol with good agitation. The precipitate of the hydrochloride is removed by filtration, washed with ether and dried. After recrystallization from methyl ethyl ketone, B-diethylaminoethyl p-methallyldiphenylacetate hydrochloride forms colorless crystals melting at 153.5-155 C. The basic ester has the formula 120 parts of B-diethylaminoethyl fi-methallyldiphenylacetate and '76 parts of ethyl bromide in 160 parts of methyl ethyl ketone are heated in a closed vessel at 100 C. for four hours. Upon chilling colorless plate-like crystals separate, which are collected on a filter, washed with methyl ethyl ketone and dried. The quaternary ammonium salt, B-triethylaminoethyl fi-methallyldiphenylacetate bromide, melts at 173-175 C.

E rample 3 p-Diethylaminoethyl allyldiphenylacetate is prepared by the method of Example 1 using 345 parts of allyldiphenylacetic acid, 189 parts of c-diethylaminoethyl chloride, and 4000 parts of isopropanol. It distills at 197-205 C. at 1.5 mm.

pressure. It forms a hydrochloride which melts at 114115.5 C. It has the formula CuHa on2=cH crn-o-o o o-omorrkmmm):

(IJQH5 Example 4 parts of B-diethylaminoethyl allyldiphenylacetate and 50 parts of ethyl bromide are reacted at C. for four hours in parts of methyl ethyl ketone. The crystalline quaternary ammonium salt is removed by filtration, washed with methyl ethyl ketone and dried. B-triethylaminoethyl allyldiphenylacetate bromide forms colorless crystals which melt at 146-150 C.

Example 5 B-Diethylaminopropyl allyldiphenylacetate is prepared as in Example 1 from 300 parts of allyldiphenylacetic acid, 180 parts of fi-diethylaminopropyl chloride and 4000 parts of anhydrous isopropanol. It is a colorless oil which distills at 187198 C. at 0.5 mm. pressure. It forms a crystalline hydrochloride which melts at 120- C. after recrystallization from a mixture of methyl ethyl ketone and ether. It has the formula CaH5 oi12=oH-cm+-oooornoH-N cs1, 2

C0115 CH3 Example 6 p-Dibutylaminoethyl allyldiphenylacetate is produced from 134 parts of B-dibutylaminoethyl chloride, 175 parts of allyldiphenylacetic acid and 250 parts of dry isopropanol, according to the method of Example 1. It is a viscous, nearly colorless oil which distills in the range of 207-2l2 C. at 1 mm. pressure. It has the formula CuHs CH2=CHCHzCO0CH2CH2N(C H9);

Example 7 o-Dimethylaminoethyl crotyldiphenylacetate is made by the method of Example 1 from parts of crotyldiphenylacetic acid, 65 parts of fi-dimethylaminoethyl chloride and 200 parts of dry 'y-Diethylaminopropyl allyldiphenylacetate is made as above from 200 parts of allyldiphenylacetic acid, 120 parts of -diethylaminopropyl chloride and 270 parts of anhydrous isopropanol. It distills at 197-200 C. at 1 mm. pressure. It has the formula CaHs 252 parts of allyldiphenylacetic acid are converted to the acid chloride by reaction with 410 parts of thionyl chloride in 2400 parts of carbon tetrachloride, as in Example 6. After removal under vacuum of the excess thionyl chloride and the solvent, the residue of allyldiphenylacetyl chloride is taken up in 350 parts of anhydrous ether. To this solution are added with eflicient agitation 1A5 parts of 6-diethylaminobutanol. The precipitate of t-diethylaminobutyl allyldiphenylacetate hydrochloride is separated and dissolved in warm water. The aqueous solution is chilled, washed with ether, then made alkaline and extracted with ether. The ether extract is washed with water and dried and evaporated. The residue of t-diethylaminobutyl allyldiphenylacetate is distilled at about 196-202 C. at 0.5 mm. pressure. It is a viscous lightcolor-ed oil. It has the formula I claim: 1. A member of the group consisting of (a) basic esters of the formula wherein R and R are members of the group consisting of hydrogen and lower alkyl radicals, Ar and Ar are monocyclic aromatic carbocyclic radicals, Alk is a lower alkylene radical and X and X are lower alkyl radicals, and (b) acid addition salts and (c) quaternary ammonium salts thereof.

2. A salt of a basic ester of the formula wherein R. and R are lower alkyl radicals, Ar and Ar are monocyclic aromatic hydrocarbon radicals, Alk is a lower alkylene radical and X and X are lower alkyl radicals.

3. A salt of a basic ester of the formula wherein R is a lower alkyl radical, Ar and Ar are monocyclic aromatic hydrocarbon radicals, All: is a lower alkylene radical and X and X are lower alkyl radicals.

4. A salt of a basic ester of the formula Ar /X OHz=CH-CHzC-G o AlkN wherein Ar and Ar are monocyclic aromatic hydrocarbon radicals, All: is a lower alkylene radical and X and X are lower alkyl radicals.

5. A salt of a basic ester of the formula 6 wherein Ar and Ar are monocyclic aromatic hydrocarbon radicals, All: is a lower alkylene radical and X and X are lower alkyl radicals.

6. A salt of a basic ester of the formula wherein Alk is a lower alkylene radical and X and X are lower alkyl radicals.

'7. A salt of a basic ester of the formula wherein Alk is a lower alkylene radical and X and X are lower alkyl radicals.

8. A salt of a basic ester of the formula wherein A and X. are lower alkyl radicals 9. A salt of a basic ester of the formula can5 l om=ooei -ooooinoii2-N l CH3 wherein X and X are lower alkyl radicals. 10. A salt of a basic ester of the formula REFERENCES CITED The following references are of record in the file of this patent:

Larsen et al., J. Am. Chem. Soc. 71, 532-533 (1949). 

1. A MEMBER OF THE GROUP CONSISTING OF (A) BASIC ESTERS OF THE FORMULA 